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Glutamine Supports Pancreatic Cancer Growth Through a Kras- Regulated Metabolic Pathway

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Glutamine Supports Pancreatic Cancer Growth Through a Kras- Regulated Metabolic Pathway Glutamine supports pancreatic cancer growth through a Kras- regulated metabolic pathway The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Son, J., C. A. Lyssiotis, H. Ying, X. Wang, S. Hua, M. Ligorio, R. M. Perera, et al. 2013. “Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway.” Nature 496 (7443): 101-105. doi:10.1038/nature12040. http://dx.doi.org/10.1038/ nature12040. Published Version doi:10.1038/nature12040 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11878814 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2013 October 04. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Nature. 2013 April 4; 496(7443): 101–105. doi:10.1038/nature12040. Glutamine supports pancreatic cancer growth through a Kras- regulated metabolic pathway Jaekyoung Son1,#, Costas A. Lyssiotis2,3,11,#, Haoqiang Ying4, Xiaoxu Wang1, Sujun Hua4, Matteo Ligorio8, Rushika M. Perera5, Cristina R. Ferrone8, Edouard Mullarky2,3,11, Ng Shyh- Chang2,9, Ya’an Kang10, Jason B. Fleming10, Nabeel Bardeesy5, John M. Asara3,6, Marcia C. Haigis7, Ronald A. DePinho4, Lewis C. Cantley2,3,11,*, and Alec C. Kimmelman1,* 1Division of Genomic Stability and DNA repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 2Department of Systems Biology, Harvard Medical School, Boston, MA 02115 3Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115 4Departments of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030 5Cancer Center, Massachusetts General Hospital, Boston, MA 02114 6Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115 7Department of Cell Biology, Harvard Medical School, Boston, MA 02115 8Department of Surgery, Massachusetts General Hospital, Boston, MA 02114 9Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/ Oncology, Children’s Hospital Boston and Dana Farber Cancer Institute, Boston, MA, 02130 10Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 Abstract Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts1. Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes2. Indeed, the spectrum of Gln-dependent tumors and the mechanisms whereby Gln supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of Gln utilization in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid (TCA) cycle, PDAC relies on a distinct pathway to fuel the TCA cycle such that Gln-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate (OAA) by aspartate transaminase (GOT1). Subsequently, this OAA is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly *To whom correspondence should be addressed: [email protected], [email protected]. 11Current Address: Department of Medicine, Cornell Weill Medical College, New York, NY 10065, USA. #These authors contributed equally. Author Contributions: J.S., C.A.L., L.C.C., and A.C.K. designed the study, interpreted the data and wrote the manuscript. J.S., C.A.L., H.Y., and X.W. performed the experiments. J.M.A., E.M., and N.S. helped with the metabolomic studies and with S.H., M.C.H and R.A.D. assisted in data interpretation. M.L., R.M.P., C.R.F., Y.K., N.B. and J.B.F. developed essential reagents and resources. Son et al. Page 2 dependent on this series of reactions, as Gln deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced NIH-PA Author Manuscript NIH-PA Author Manuscriptglutathione. Moreover, NIH-PA Author Manuscript knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of Gln metabolism is mediated by oncogenic Kras, the signature genetic alteration in PDAC, via the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumors. The prognosis of patients with PDAC remains dismal. The disease is extremely aggressive and is profoundly resistant to all forms of therapy3. Thus, there is a strong impetus to identify new therapeutic targets for this cancer. In recent years, there has been renewed interest in understanding the altered metabolism in cancer, and how such dependencies can be targeted for therapeutic gain. However, achieving a successful therapeutic index remains a major challenge to the development of effective cancer therapies that target metabolic pathways. Recent evidence demonstrates that some cancer cells utilize glutamine (Gln) to support anabolic processes that fuel proliferation2. However, the importance of Gln metabolism in pancreatic tumor maintenance is not known. Thus, we sought to explore the dependence of PDAC on Gln, and to examine the functional role of Gln in PDAC metabolism. As expected from our previous work4, glucose was required for PDAC growth. Additionally, PDAC cells were also profoundly sensitive to Gln deprivation, indicating that Gln is also critical for PDAC growth (Fig. 1a and Supplementary Fig. 1). Gln provides a carbon source to fuel the TCA cycle and nitrogen for nucleotide, nonessential amino acid (NEAA) and hexosamine biosynthesis5,6. To assess the role of Gln metabolism in PDAC growth, we first impaired glutaminase (GLS) activity using RNA interference (RNAi). Notably, GLS knockdown markedly reduced PDAC growth (Fig. 1b and Supplementary Fig. 2a, b). Consistent with this observation, Glutamate (Glu) was able to support growth in Gln-free conditions (Supplementary Fig. 2c). Glu can be converted into α-ketoglutarate (αKG) to replenish the TCA cycle metabolites through two mechanisms1; either by glutamate dehydrogenase (GLUD1) or transaminases (Fig. 1c). Indeed, many cancer cells rely on GLUD1-mediated Glu deamination to fuel the TCA cycle7, and αKG has been shown to be an essential metabolite in Gln metabolism8. Surprisingly, dimethyl αKG9 did not restore growth upon Gln deprivation (Fig. 1d), whereas the combination of αKG and an NEAA mixture (the output of transaminase- mediated Glu metabolism) dramatically rescued proliferation in multiple PDAC lines (Fig. 1d and Supplementary Fig. 2d, e). Together, this data suggests that PDAC cells metabolize Gln in a manner that is different from canonical models10 and that this class of enzymes may be critical for Gln metabolism in PDAC. To confirm the importance of transaminases in PDAC Gln metabolism, we treated PDAC cells with either aminooxyacetate (AOA), a pan-inhibitor of transaminases11, or epigallocatechin gallate (EGCG), an inhibitor of GLUD112. While EGCG had no effect on PDAC growth, AOA treatment robustly inhibited the growth of multiple PDAC cell lines (Supplementary Fig. 3). Consistent with these results, GLUD1 knockdown also had no effect on PDAC growth (Fig. 2a). To identify the specific transaminase(s) involved in PDAC Gln metabolism, we inhibited a panel of Glu-dependent transaminases (aspartate, alanine and phosphoserine transaminase) individually using RNAi and examined the effect on PDAC growth. Interestingly, knockdown of the aspartate transaminase GOT1 Nature. Author manuscript; available in PMC 2013 October 04. Son et al. Page 3 significantly impaired PDAC growth in multiple PDAC cell lines and primary PDAC cells (Fig. 2a and Supplementary Fig. 4, 5). NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript We next explored the direct effects of GOT1 on Gln metabolism by performing targeted metabolomic analysis in GOT1 knockdown PDAC cells using uniformly 13C-labeled Gln 13 4,13 ([U- C5]-Gln) as a tracer . GOT1 catalyzes the conversion of aspartate (Asp) and αKG into OAA and Glu in the cytoplasm. Indeed, GOT1 knockdown led to increased Gln-derived Asp (and total Asp) and decreased OAA (Fig. 2b and Supplementary Fig. 6a). Interestingly, we also observed a significant decrease in the ratio of reduced-to-oxidized glutathione (GSH:GSSG; Fig. 2b and Supplementary Fig. 6b), suggesting that GOT1 may play a role in the maintenance of cellular redox homeostasis. It should be noted that the changes in metabolite abundance described in this experiment are representative of the total cellular metabolite pool, due to technical limitations associated with organelle-specific metabolite isolation. Importantly however, the results we obtained are consistent with what one would expect if flux through GOT1 was
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